The restricted expression of specific hepatic genes in pericentral or periportal regions of the adult liver, a phenomenon known as zonal regulation, is a fascinating aspect of liver biology. Elegant studies in the past 10 years have uncovered the role of the b-catenin signaling pathway in controlling zonal expression. Our recent studied using a novel mouse model system developed by us indicates that the retinoic acid-related orphan receptor alpha (RORa) also plays a role in controlling zonal gene expression. Furthermore, studies in other tissues have shown that RORa contributes to the differentiation and proliferation of stem cells, but this property has not been evaluated in the liver. We propose to use genetically modified mice and contemporary high- throughput genomic technologies to explore the role of RORa in the function and stem cell properties of pericentral hepatocytes. Since many hepatotoxins, including ethanol, and pharmaceuticals, such as acetaminophen, specifically damage pericentral hepatocytes, a better understanding of the mechanisms controlling gene expression in and the self-renewing properties of this subpopulation of hepatocytes will help develop strategies to reduce hepatocyte injury in humans.